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ADVENTRX restarts 505(b)(2) development

Published June 29th, 2009 in News Commentary. 0 Comments

Today June 29, ADVENTRX Pharmaceuticals announced plans to use their recent financing to finish the development of ANX-530 (vinorelbine emulsion) and submit a 505(b)(2) NDA by the end of the year.

Careful readers of this blog may remember a January 2008 posting citing ADVENTRX ANX-530 as an example of where a single pk study might be sufficient for an NDA. The company’s recent press release suggests that there are manufacturing issues needed to complete the filing.

Like many companies, ADVENTRX has had difficulties raising capital to fund its drug development projects. Last month, the company reported disappointing results for its ANX-514 (docetaxel emulsion) product - it failed to meet the usual bioequivalence standards. A 505(b)(2) is not subject to the same statutory goalposts (80 -125% ) as a generic drug but there must be justification for small excursions outside these limits. It is unclear from the press release whether the company had a prior agreement with the Agency to meet these limits.

Make the Most of Your Interactions with the FDA: FDA Meeting Requests

Published June 29th, 2009 in 505(b)(2) Process. 0 Comments

Any meeting with the FDA is critically important to Sponsors. We all know that a tremendous amount of time and effort goes into planning for these meetings. But even before this step the decision to ask for a meeting and the contents of the meeting package should be carefully considered.

Typically, a meeting is requested to gain insight and direction about the development plans that a Sponsor has defined. On its face this sounds easy. This all depends on how clear a Sponsor is about the current status of the program and what tasks are defined in the path ahead. In addition, keep in mind the new guidance from the FDA “Formal Meetings Between the FDA and Sponsors or Applicants“.

A meeting request with the list of questions can be submitted to the Agency ahead of a meeting package. The sooner the meeting package is provided to the Agency the better. You may decide prior to the meeting to change the questions, if it occurs before the meeting package is forwarded this is no problem. The questions can deviate from the initial meeting request information and the meeting package should provide the background for the new questions.

However if you decide to change the questions after the meeting package has been submitted, then a discussion should occur with the project manager. If there change can still be supported by the meeting package submitted this would be a minor change. If the change requires additional background material this must be discussed based on the amount of information and the time remaining before the meeting.

It can happen that additional questions come to mind during the meeting and a new direction should be probed. There are limits to how far from the meeting package you can deviate. The purpose of the package is to provide specific background to allow the agency to see many sides of the question being addressed and make an informed commentary on the question being asked. Obvious extensions of the existing list of questions could be allowed but the request should be stated as outside the planned discussions for the meeting minutes.

Even when the Agency provides an answer to specific questions, references to the guidance documents and language that these will be review issues may always be inserted into the meeting minutes to protect the Agency.

When can you actually get an answer to your question? When you have provided various sides to the arguments, thought through all possible outcomes and provided the Agency with a safe and reasonable path, then there is the possibility that you will get concurrence. You must pose the question such that the Agency understands what you are basing the question on and provide the path for the Agency to come to an agreement. The more advanced the program the potential exists to obtain specific answers from the Agency.

If the information provided in the package is vague, the answer will most likely be: this is a review issue. When the questions posed to the Agency are open ended or call for decisions on uncharted territory, it will be difficult to get a specific answer.

The following are Camargo’s Guidelines for Discussion with FDA:

The FDA Project Manager runs the meeting from the FDA side and the Sponsor should have one primary person defined ahead of the meeting.
Be on time or early.
Review all the questions that have been submitted to the FDA and prepare the answers.
The Sponsor’s primary will assess the topic (or review the agenda if available) and will ask individuals to address the answer to questions when appropriate.
Do not address any business or financial impacts. Do not even mention this.
Do not argue.
Be open and honest in answering questions or discussing points that the FDA is interested in.
Do not hold information back.
Do ask for clarification or ask to understand the FDA’s viewpoint when you are unclear on a discussion point, (typically the Sponsor’s primary will do this, but others can be asked by the primary to answer a question, then it is appropriate for that person to speak).
The Sponsor should assign a note taker and will provide unofficial notes. To be clear, the FDA meeting minutes are the only official record.
If the FDA asks a question that we need discussion internally on before answering, we will ask to get back to them on the following Monday.
The Sponsor is the final decision maker for the program. No decisions have to be made during an FDA meeting and it is appropriate to define a timeframe for responding to specific requests.

Linking Preclinical (Safety), Clinical (Efficacy) and CMC (Quality) Development Activities

Published June 26th, 2009 in 505(b)(2) Process and CMC Issues. 0 Comments

Camargo is often called on to write and/or assemble NDAs. When we get to prepare an NDA from the beginning, all of the information builds and the resulting ’story’ is easy for the FDA to understand. Often we are retained to write portions and just insert portions written by third parties. Gaps can ensue. Lyn Gold, VP CMC, adds some cautionary words below.

Linking Preclinical (Safety), Clinical (Efficacy) and CMC (Quality) Development Activities

A regulatory file is separated into modules much like the ICH common technical document. Often one team member is responsible for the preclinical module (Nonclinical Summaries Module 2 and Safety Module 4), one team member is responsible for the clinical module (Clinical Overview and Clinical Summary Module 2 and Efficacy Module 5) and one team member is responsible for the CMC modules (Quality Overall Summary Module 2 and Quality Module 3). Somehow, because they are modular, the fact that they are interdependent often gets lost in the process of assembling the regulatory application. You will notice that Module 2 brings them all together, capturing high level summaries of the critical components of each section. Details on the contents of the ICH common technical document can be found here.

A 505(b)(2), by definition, relies heavily on literature to support the regulatory strategy and potentially streamline the studies required to support the application. The preclinical and clinical modules are somewhat forced to interact due to the fact that much of the data driving the clinical studies in humans are gleaned from the preclinical and clinical literature for safety and toxicology.

The CMC modules of a regulatory application often are written as standalone components of the file. If the sponsor can weave the thread connecting the CMC modules to the preclinical and clinical modules the regulatory application becomes a coherent story. When the formulation that was studied in the PK bridging study for a new dosage form is compared to the RLD is the same formulation (meeting the same specifications) as that in the final application, the conclusions from the study can be relied on. It is not unusual for development programs to have a formulation change or a specification change that occurs along the path of a preparing a regulatory submission. This can all be managed provided the changes are documented and the impact of the change is evaluated and supported by data. Providing a connection from the old to the new with a data trail is the best way to ensure the Agency that the development history of the product in the application.

The connection from the drug product (all CMC components) to the clinical trial data and the supportive preclinical data is the heart of the application for the Agency. If this connection is clear and seamless, the data will speak for the application. When the sponsor can’t make this connection, then the question should be asked, “What else is needed to connect the data?”. Remind the reviewer of the critical connections as the modules are complied. This will provide an easier path to understanding the development plan and hopefully the proposed product safety and efficacy.

ANDA Suitability Petition vs 505(b)(2)

Published June 12th, 2009 in 505(b)(2) Process and ANDA's. 0 Comments

I was honored to be invited to speak at the FDA-OCRA 12th Annual Educational Conference in Irvine California on June 10, 2009. I was asked to discuss and compare the 505(b)(2) and ANDA Suitability Petition. I thought I should share this topic with the readers of this blog.

Why make the comparison between an ANDA Suitability Petition and a 505(b)(2)? Because both allow for changes from a reference listed drug (RLD).

I assume we all know that an ANDA product is the same as the RLD and is governed by 505j. Yet, the same Hatch-Waxman amendments in 1984 provided for a suitability petition that allows the following differences in an ANDA product:

A different active ingredient in a combination product in which the other active ingredients match those of the RLD
A different route of administration
A different dosage form
A different strength

Hold it! Aren’t these differences spelled out for 505(b)(2) differences too?

The bottom line is that an ANDA can contain only those differences that do not need clinical evidence for efficacy and safety. It turns out that most changes need clinical studies so there are very few approved ANDA suitability petitions.

An ANDA suitability petition is a petition (request) to FDA to permit the filing of an ANDA for a drug that differs from the RLD. Thus, you must have an approved suitability petition in order to file an ANDA with the proposed differences. The law doesn’t do a good job at laying down the process for these petitions, but FDA handles them like Citizen Petitions. That is, the process includes:

File petition
Public Docket
Public Input
FDA OGD/CDER Review
Decision published
If Petition is approved, ANDA may be filed

Thus, the ANDA suitability petition is a very public process. Many pharma companies use consultants or their legal firms to file in order to avoid publicity. Note that once a suitability petition is approved, anyone can use the approval to file for the same change.

The law provides for a 90-day review but that never happens. Because OGD needs to have CDER’s input, and CDER’s priority is the PDUFA drugs, reviews can take a long time (we are going on 3 years for a suitability petition for one of our clients).

The petition itself is rather simple. It contains the requested change, the reason the change should be accepted or denied (like any governmental petition, both favorable and unfavorable information must be included) and the proposed labeling. It is not the ANDA and FDA’s approval of a suitability petition doesn’t mean it will approve the ANDA when filed (meaning it could change it’s decision).

The listing of petitions is on the FDA website. An excerpt will help us illustrate the grounds for approval and denial:

anda-suitability-docket

The excerpt above shows petitions that are pending, approved and denied. The process is such that a petition is approved if it is not denied, so let’s look at the reasons for denial:

Changes to an API in a single ingredient product
The petition does not contain information to show that the different active ingredient of the drug product is of the same pharmacological or therapeutic class as the ingredient of the RLD
The different active ingredient is not an active ingredient in a listed drug
The remaining active ingredients are not identical to those of the listed combination drug
Any of the proposed changes from the listed drug would jeopardize the safe or effective use of the product so as to necessitate significant labeling changes to address the newly introduced safety or effectiveness problem
FDA has determined that the RLD has been withdrawn from sale for safety or effectiveness reasons

As I wrote above, basically the reason for denial is that the proposed change raises efficiacy or safety issues that must be addressed via clinical studies - that is, the changes must be submitted and reviewed under 505(b)(2).

Let’s look at the examples above.

Approval: Triax Pharmaceuticals submitted a suitability petition as follows:

RLD: Retin-A (Tretinoin) Cream, 0.025%, 0.05%, and 0.1 %, Johnson & Johnson
Proposed Change: two intermediate strengths 0.0375% and 0 .075%
Basis for Approval: The Agency has determined that sameness of therapeutic effect for these two interim strength Tretinoin Cream products can be demonstrated using comparative bioavailability data

Denial: Lachman Consultant Services submitted a suitability petition as follows:

RLD: UltramB (Tramadol Hydrochloride) Tablets, 50 mg, Ortho-McNeil Pharm, Inc
Proposed change: Tablets to Oral Solution
Basis for denial: (a) PREA. UltramB is not labeled for pediatric use; clinical studies would be required and (b) clinical trials needed for oral solution due to uncertain pk/pd relationship

Generally speaking, changes that are approvable are dose changes. While at Duramed, we obtained approval for several products, for example, where the RLD had scored tablets or intermediate dosage strengths where the RLD labeled dose was 2 tablets or capsules.

ANDA suitability petitions were quite popular in the late 1980’s and 1990’s because FDA determined that many changes didn’t require clinical studies. This changed with the advent of pediatric initiatives. In 1999 Congress passed what is known as the Pediatric Rule. The applicable part is:

“… each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration shall contain data that are adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations.” 21 CFR 314.55(a)

As if there was any question that this applied to ANDA suitability petitions, FDA covered it:

“… if a petition is submitted for a change that would require a pediatric study under this rule, the petition may be denied.” 63 Fed. Reg. at 66641 (FDA response to Comment 10)

The Pediatric Research Equity Act (PREA) of 2003 and renewed and extended by Title IV of 2007 FDAAA, stipulated that an assessment was required for all applications submitted after April 1999 containing a:

new active ingredient
new indication
new dosage form
new dosing regimen, or
new route of administration

Indeed, PREA caused FDA in early 2007 to rescind approval of about (there were errors so the exact number is changing) 128 suitability petitions:

”FDA had approved these suitability petitions to permit ANDAs to be submitted for drugs that had a different active ingredient, dosage form, or route of administration than their RLDs. However, these approval decisions are being withdrawn because ANDAs were never submitted and PREA requires that all applications submitted on or after April 1, 1999, for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration contain an assessment of the safety and effectiveness of the drug for the claimed indications in relevant pediatric subpopulations.” 72 FR 8184 23Feb2007 (edited for brevity)

The applicable regulations are at 21 CFR 314.93.

Electronic filing of eCTD INDs

Published June 9th, 2009 in 505(b)(2) Process and How to:. 0 Comments

As large amount of documentation and data are required in IND submissions, the Electronic Common Technical Document (eCTD) format is a wise choice for the submission of INDs to the FDA. Camargo’s experience with filing INDs in the eCTD format includes a very recent eCTD IND application accepted by the FDA’s Division of Anesthesia, Analgesia & Rheumatology Products (DAARP).

Because submission of eCTD INDs requires an e-CTD software package, keep in mind that several versions are available from different vendors. Although applicants can use many different approaches to filing an eCTD IND, Camargo strategy in filing eCTD INDs involves the following steps:

Documents are written in Microsoft WORD files using templates based on ICH eCTD guidances;
PDF documents created from the WORD documents mentioned above;
The PDF documents are loaded onto an XML backbone
Once finished loading the files, the software validates the XML files including backbone and Study Tagging File against DTD format guidelines and allows the entire application to be exported as a submission.
The resulting document submission can then be burned to a CD. It is important to note that not all CD burner software work may work properly when handling these files.

Writing and submitting electronic 505(b)(2) INDs

Published June 8th, 2009 in 505(b)(2) Process and How to:. 0 Comments

Any use of a drug product not previously authorized for marketing in the United States first requires submission of an Investigational New Drug Application (IND) to the FDA. To date, the FDA accepts IND submissions in the ‘old format‘ and in the Common Technical Document (CTD) format. The CTD is maintained by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and is designed to be used by regulatory agencies across the 3 regions, namely Europe (European Medicines Agency, EMEA), Japan (the Ministry of Health, Labour and Welfare) and the United States (FDA). As drug development becomes more complex and tightly regulated, the CTD is becoming the choice IND format for registration of human pharmaceuticals by many applicants. In our experience, one practical advantage of preparing INDs in the CTD format is that it allows the starting point for building into an eventual NDA. Therefore, the CTD format in particularly appropriate for those applicants using the 505(b)(2) pathway, where large amounts of pre-existing information need to be incorporated and the time from IND to NDA submission may be short.

INDs in the CTD format can be submitted to the FDA in paper or electronically (eCTD). The content organization of both paper CTD and eCTD are identical, with the only obvious difference that paper is not involved in the eCTD. Also, if filing an IND in eCTD format, all the future applications must be submitted electronically. This basic characteristic of the eCTD format can be a major advantage. For example, because the IND application can range from hundreds to several thousands of pages, the eCTD format significantly reduces time and resources used to compile a paper application. Very useful features of the eCTD include hypertext links and bookmarks, which allow easier navigation through a large IND document.

When writing an IND in eCTD format, you must first familiarize yourself with its organization. A great place to start is by consulting the guidances issued by the ICH, particularly “M4: Organization of the CTD“. For those familiar with the ‘old format’, the FDA provides the Comprehensive Table of Contents Headings and Hierarchy indicating where sections of the CFR Citation (’old format’) should go in the CTD document. Basically, the CTD/eCTD is organized in 5 modules: Module 1 (Administrative Information and Prescribing Information), Module 2 (Common Technical Document Summaries), Module 3 (Quality), Module 4 (Nonclinical Study Reports), and Module 5 (Clinical Study Reports). Module 1 is specific to each of the 3 ICH regions (Japan, Europe, and the United States). Module 2 should include a general introduction to the pharmaceutical (normally not exceeding one page), nonclinical overview and summaries, and clinical overview and summaries.

As with any other IND submission, the information provided in the eCTD should be unambiguous and transparent. This should help a reviewer to become quickly oriented to the application contents and should facilitate the review of basic pharmaceutical data.

Risk Evaluation Mitigation Strategy (REMS) for long-acting opioids

Published June 4th, 2009 in 505(b)(2) Process, Formulation Issues and News Commentary. 0 Comments

Camargo is working with several clients in developing better treatments for pain. Unfortunately, the active substances that supress pain also can be abused. The FDA and DEA are trying to find ways to allow access to these medicines while imimizing the inherent risks of drug abuse.

In order to properly advise clients, Camargo attends various industry/FDA meetings. The following is a summary from one of our Research Scientists, Kristin Jones, PhD.

The Food and Drug Administration (FDA) heard testimony on May 27 and 28, 2009, regarding the effort to develop a class-wide Risk Evaluation Mitigation Strategy (REMS) for long-acting opioids products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone or oxymorphone. The public hearing was held to get input from industry, healthcare providers, researchers, patient advocates, and pharmacies on what a REMS should like for these products, how to minimize the burden on the health care community and patients while achieving the objective of ensuring that the benefits of these drugs outweigh the risks, and how FDA should evaluate the REMS to determine whether it is achieving these objectives. Under the Food and Drug Administration Amendments Act of 2007 (FDAAA; Public Law 110-85), the FDA has the authority to require a REMS when necessary, to ensure the benefits of a drug outweigh the risks.

Opioid drugs are a beneficial and necessary component of pain management in patients who suffer from chronic pain. However, these drugs have serious risks when not used properly. Previously, the FDA and drug companies have taken steps to prevent misuse and abuse of opioid drugs. Despite these efforts, the rates of misuse, abuse, and overdosage continue to increase. Establishing a REMS for opioids is intended to reduce these risks, while ensuring that patients who legitimately need these medications maintain appropriate access to them.

According to Gregory Terman, MD, PhD, a representative from the American Pain Society, a REMS should: 1) cover all opioid classes; 2) have no required patient registry; 3) contain components that are measurable and easily reversible, when necessary; 4) require prescribers and dispensers to demonstrate their knowledge of opioid pharmacology; and 5) contain education programs targeted toward the public (eg, the dangers in sharing opioids).

Representatives from the Industry Working Group, which consists of 25 companies who market short- and long-acting opioids, presented the following points: 1) a successful REMS should not interfere with effective treatment of patients; 2) success needs to be defined; and 3) it is necessary to ensure that the outcomes of REMS can be measured. The Industry Working Group proposed that the REMS include: 1) product specific medication guides written in plain language, including tear-away wallet cards; 2) specific communication plans for healthcare providers, pharmacists, professional societies, DEA, FDA, trade journals, state licensing boards, Federation of State Medical Boards; 3) elements to insure safe use including prescriber education, training, certification, dispenser education, training and certification, and signed prescriber-patient agreements.

In the opinion of representatives from the generic companies Roxane Laboratories and Covidien, the REMS process has favored innovator companies. For example, the medication guides follow the “brand first” labeling process and prescriber training is conducted through the “brand” sales force. In addition, they stated that current surveillance measures do not identify products by dosage form, strength, or manufacturer. In their opinion, there should be a single-shared system and REMS should be grounded in patient safety, where prescriber training is not provided by the sales force and ANDA holders have input into the patient medication guide.

Representatives from Roxane Laboratories and Covidien also argued that methadone should have its own REMS for the following reasons: it is not formulated as a sustained-release product; it has both pain and addiction treatment indications, while other opioids are only indicated for pain; methadone prolongs the QTc interval, which does not occur with other products.

Several groups (eg, American Pain Foundation, risk management professionals, the Industry Working Group) recommended that the REMS should begin with a pilot. A representative from a company that implements and tracks REMS predicted that the development of such a program with participation by approximately 25 companies would probably take at least 1 year.

Throughout the 2-day meeting, the FDA panel members repeatedly expressed concerns about:

What should the metrics for the REMS be and how should success be measured?
What baseline data for the REMS exist?
What educational measures have been used successfully?
What data exist to support the success of educational measures?
How do we find a balance between the “need for immediate action” and the call to “not do anything until we can do it right”?

How will this opioid REMS affect drug companies considering using the 505(b)(2) regulatory pathway for development of opioid products (eg, modified release, change in formulation, novel combination)?

A REMS for opioid products will likely result in a delay in product approval while a class REMS is under development
This REMS could facilitate or discourage new drugs and dosages from development
This REMS is likely to place restrictions on prescribing, distribution, and dispensing of opioid drugs
There will likely be an increased cost for REMS compliance, a possible need to contribute to databases, possible registries for patients using opioids, mandatory certification for prescribers and dispensers, increased patient education, and increased continuing education requirements

FDA maintains a web site summarizing actions to date.

Melphalan - New 505(b)(2) Orphan Designation

Published June 4th, 2009 in News Commentary. 0 Comments

Delcath Systems Inc. announced that the FDA has granted an additional orphan designation for melphalan for the treatment of neuroendocrine tumours metastatic to the liver. Delcath uses a proprietary system they call the Percutaneous Hepatic Perfusion (PHP) System to deliver high doses of existing drugs directly to the site of the tumor. Melphalan was first approved in 1964 in a tablet form under the brand name Alkeran by GSK for the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. It was subsequently developed as an injection and approved in 1992 with an orphan indication for systemic administration for palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

This is a great example of taking an older drug, improving it and even getting an orphan indication. This gets 7 years of data exclusivity upon approval.

Cheerios® – breakfast cereal or…drug?

Published June 2nd, 2009 in News Commentary. 0 Comments

Cheerios® - venerable breakfast cereal or…drug? Last month the FDA issued a warning letter to General Mills CEO Ken Powell, informing him that the cholesterol-lowering claims on the Cheerios label transformed it from food product to unapproved drug. The Food and Drug Administration Modernization Act of 1997 allows for certain authoritative health claims to be made on food products (see FDA Guidance). The exact wording of the claim and a description of the scientific evidence upon which the claim is based must be approved by the FDA before the claim appears on a marketed product, and such claims may not attribute any degree of risk reduction. The Cheerios label does contain an authorized health claim about soluble fiber/coronary heart disease (21 CFR 101.81). However, the Cheerios label also contains the statement, “You can lower your cholesterol 4% in 6 weeks.” This claim of a degree of risk reduction was a major factor in the FDA’s decision to classify Cheerios with the cholesterol-lowering claim in its label as a drug.

This incident brought to mind the situation of dietary supplements. In contrast to foods, the Dietary Supplement Health and Education Act of 1994 (DSHEA) allows certain types of claims to be made about the uses of dietary supplements without prior review of the statement (65 FR 999, 6 January 1999). These statements are generally referred to as “structure/function claims” and include, among other things, statements that describe the role of a nutrient or dietary ingredient intended to affect the structure or function in humans or that characterize the documented mechanism by which a nutrient or dietary ingredient acts to maintain such structure or function [21 CFR 101). DSHEA also amended the Federal Food, Drug, and Cosmetics Act to reflect the fact that dietary supplements that contain such statements are not to be considered as drugs. But cross the line and make a disease-related claim about a dietary supplement and the supplement is then considered to be a drug.

So what happens when a company wants to combine a dietary supplement with an over-the-counter (OTC) or Rx drug? In October 2001, warning letters were issued to 2 pharmaceutical companies who tried to market products that combined acetaminophen (an OTC drug) with dietary supplements. It has been legal to market acetaminophen without an NDA since the publication of a 1977 report that recommended acetaminophen be considered GRASE (42 FR 35346). As dietary supplements, melatonin and glucosamine could also be legally marketed without prior approval under DHSEA. However, under section 403 dietary supplement claims "may not claim to diagnose, mitigate, treat, cure, or prevent a specific disease or class of disease" except for certain classical nutrient deficiency diseases. In addition, dietary supplement products may not contain any ingredients that are drugs, unless the drug was marketed as a dietary supplement before it was approved as a drug. The presence of an approved drug (acetaminophen) in the finished product and the disease claims for the supplement portions of these products caused them to be ruled unapproved drugs.

On May 30, 2000, the FDA issued letters about the regulatory status of products that combine an over-the-counter drug with a dietary supplement. In these letters, the FDA stated, "The agency must determine under what conditions these combination products can be marketed in accordance with the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by DSHEA. More specifically, the agency must determine what regulatory standards are appropriate, including, but not limited to, what safety and effectiveness standards will apply and how such products will be labeled." The FDA also asked firms to refrain from marketing products that combine both drug and dietary supplement ingredients, except for products marketed under an approved NDA, "until the agency has carefully considered these issues", and stated that "The number of inquiries we have received on this subject has made resolution of these issues a priority at the agency [emphasis added]. We will be providing additional information as we develop our policy in this area.” However, nearly a decade later, regulatory standards have still not been determined. The issue continues to be a problem, as evidenced by a similar warning letter that was recently issued to the manufacturer of BAYER WOMEN’S Low Dose Aspirin + CALCIUM (27 October 2008).

What are DESI Drugs?

Published June 1st, 2009 in 505(b)(2) Issues. 0 Comments

A reader pointed out that I have never defined DESI drugs, despite several posts that contained references to them. DESI drugs are a great source for 505(b)(2) development since many will qualify for 5 years data exclusivity.

Once upon a time….

In 1938 the FD&C Act was established that required that drugs be proven safe before coming to the market. It wasn’t until the Kefauver-Harris Amendments to the Act in 1962 that drugs also had to be proven efficacious before they could be approved. The passage of this law created a problem - what about all of the products that had been approved under NDA’s between 1938 and 1962 that were on the market? In addition to these NDA-products, there were a large number of “ identical, related, and similar” products to such drugs. The answer was that the products could stay on the market but would be reviewed and ‘approved’. Unfortunately, FDA did not have the resources to conduct this review so in 1966 a contract was made with the National Academy of Sciences/National Research Council. In 1968 FDA set up a process called DESI - Drug Efficacy Study Implementation, to implement the recommendations of these reviews.

The gist of the process was to have teams review existing information and decide on the medical and scientific merits of the product, classifying the drugs as effective, ineffective, or needing further study. FDA would review these recommendations and publish the findings. The teams were academics, medical professionals and government employees. These teams reviewed classes of drugs by therapy rather than individual drugs (in 1973 the Supreme Court concurred with this approach). The information relied on was labeling, publications and information from sponsors and the opinion of the team members. The FDA publishes its conclusions in the Federal Register.

How did they do? The great unanswered and unanswerable question. Nobody, including FDA, knows how many DESI products there were/are. People ask me for a list. Nobody has a complete list. Nor is DESI complete! There are many groups of drugs for which no DESI notice has been published - in 2007 FDA estimated about 20 categories are left in some stage of review or notice. Moreover, many of these products and/or labeling have changed over the years so it is a moving target.

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