Independent Laboratory Testing Demonstrates Important Quality Differences Between FDA-Approved Makena® and Compounded 17P Formulations

 

 

FDA Issues Statement on Makena® on November 8, 2011

ST. LOUIS, Nov. 8, 2011 /PRNewswire/ -- Recent testing conducted by independent laboratories, commissioned by Ther-Rx Corporation, a subsidiary of K-V Pharmaceutical Company (the "Company") (NYSE: KV.A/KV.B), shows that multiple samples of both compounded 17P drug formulations and active pharmaceutical ingredient (API) that may be used in compounded 17P failed to meet certain established standards for potency and purity. These findings, which have been submitted to the U.S. Food and Drug Administration (FDA), demonstrate important quality differences in these compounded 17P formulations when compared to FDA-approved Makena® (hydroxyprogesterone caproate injection).

"We commissioned this research because moms and healthcare providers deserve to know whether medications prescribed during pregnancy meet FDA's quality standards," said Greg Divis, President and CEO of K-V Pharmaceutical Company. "This research demonstrates important differences in product quality between FDA-approved Makena® and these compounded 17P formulations. Healthcare providers and patients have no practical way of ensuring that compounded 17P formulations meet FDA's quality standards. Now that FDA-approved Makena® is available, America's high-risk moms deserve a product that consistently meets FDA's standards."

On Nov. 8, 2011, the FDA issued a statement on Makena® acknowledging it has received information from the Company regarding the potency and purity of samples of bulk hydroxyprogesterone caproate APIs and compounded hydroxyprogesterone caproate products. FDA stated, "According to the analysis of this information provided by K-V, there is variability in the purity and potency of both the bulk APIs and compounded hydroxyprogesterone caproate products that were tested." The agency has begun its own sampling and analysis of compounded hydroxyprogesterone products and the bulk APIs used to make them. In FDA's statement, the agency "reminds healthcare providers and patients that before approving the Makena® new drug application, FDA reviewed manufacturing information, such as the source of the API used by the manufacturer, proposed manufacturing processes and the firm's adherence to current good manufacturing practice. Therefore, as with other approved drugs, greater assurance of safety and effectiveness is generally provided by the approved product than by a compounded product."  

The full text of the FDA statement is available athttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm279098.htm

Overview of Research

The active pharmaceutical ingredient in FDA-approved Makena®, hydroxyprogesterone caproate, is sourced exclusively from the same FDA-registered and FDA-inspected manufacturer that supplied the API used in the NICHD study that served as part of the basis for FDA approval of Makena®. To the Company's knowledge, this is the only manufacturer of hydroxyprogesterone caproate known to have an active Drug Master File with the FDA.  

Research commissioned by Ther-Rx shows that the API used in compounded 17P formulations originates primarily from facilities in China that are neither registered with nor inspected by the FDA. This research also found that the vast majority of entities claiming to be original manufacturers of hydroxyprogesterone caproate are actually re-packagers, re-sellers, brokers or distributors of hydroxyprogesterone caproate that is actually manufactured in China.

The Company also commissioned independent laboratory testing to assess samples of API and compounded 17P formulations and, as such, does not purport to assess the quality of all of the various compounded 17P formulations and hydroxyprogesterone caproate API available on the market. Specifically, the laboratory testing included:

• 10 samples of API used in compounded 17P formulations provided by 10 different suppliers of API. Seven of the suppliers were determined to be original manufacturers of API that are located in China and that, to the Company's knowledge, do not appear to have been registered with or inspected by the FDA. The other three were identified as U.S.-based resellers of API, whose product is also believed to originate from China.
• 30 vials of compounded 17P formulations, prepared by 30 different compounding pharmacies across 15 states.

The independent laboratories measured the quality of each API sample and compounded 17P vial against certain quality standards required by FDA for Makena®. The samples also were evaluated by these labs against certain U.S. Pharmacopeia (USP) standards for hydroxyprogesterone caproate and hydroxyprogesterone caproate injection, because some compounding pharmacies claim that their compounded formulations meet USP criteria. The laboratories analyzed the API and compounded 17P drug formulations to assess potency, chemical impurities and drug identity.

Key Laboratory Testing Findings

Active Pharmaceutical Ingredient (API)

• One API sample sent from a Chinese manufacturing facility was not the correct active pharmaceutical ingredient. Although the package was sent to the United States labeled in Chinese as hydroxyprogesterone caproate (HPC), the active ingredient failed the drug identity test for HPC. Further laboratory analysis conclusively proved that the substance was glucose instead of HPC.
• 80 percent (8 of 10) of the API samples failed to meet at least one FDA standard for unknown impurities.
• 50 percent (5 of 10) of the API samples failed to meet the USP standard for potency.
• The paperwork (certificates of analysis) that arrived with API shipped from China was often missing or incomplete. Such gaps in paperwork can make it difficult to track back specific product to specific manufacturing facilities, which is critically important should a problem with the medication arise.

Compounded 17P Formulations

• 27 percent (8 of 30) of the compounded 17P vials tested failed to meet the USP standard for potency. The potency values of the compounded 17P vials ranged from just over half to a level more than 2.5 times the labeled potency. If these vials were administered to patients, some patients would not have received the dose of 17P that was reviewed and subsequently approved by FDA for safety and efficacy in this patient population. This variability in potency was comparable to those found in FDA's limited survey of compounded drug products conducted in 2006, which is available at:  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm204237.htm
• 53 percent (16 of 30) of the vials of compounded 17P had levels of unknown impurities that exceeded at least one standard required by the FDA for Makena®. The potential toxic effects of these unidentified compounds in the intended patient population are unknown.  
• Taken together, two-thirds (20 of 30) of the compounded 17P vials failed to meet at least one USP requirement (a standard used by some compounding pharmacies) or at least one FDA quality standard required of Makena® for potency and/or purity levels. Information was not obtained regarding the sterility of, or potential presence of endotoxins in, the compounded 17P vials.  
• FDA-approved Makena® must meet FDA's quality standards before release for patient use.

Article is found here
.

K-V prompts FDA Investigation into Compounding Pharmacies--Makena--API Source from China

K-V prompts FDA Investigation into Compounding Pharmacies--Makena--API Source from China

To read article, click here 

Wedgewood Village Pharmacy, Inc.: The 2005 Third Circuit Decision

The Wedgewood Village Pharmacy, Inc. (Wedgewood) decision, a critical case dealing with compounding and the FDA's jurisdiction, was rendered in the Third Circuit Court of Appeals in 2005.  The Third Circuit has appellate jurisdiction over,

District of Delaware

District of New Jersey

Eastern District of Pennsylvania

Middle District of Pennsylvania

Western District of Pennsylvania

The beginning of that case provides a good summary of what the case is about.  The beginning provides:

Wedgewood Village Pharmacy appeals the District Court's order affirming the Magistrate Judge's denial of Wedgewood's motion to quash an administrative warrant issued to agents of the Food and Drug Administration.   Wedgewood argues that it is exempt from FDA inspection under provisions of the Food, Drug, and Cosmetic Act (the “FDCA”), 21 U.S.C. § 301 et seq.   Wedgewood also contends that it was denied procedural due process.  For the reasons that follow, we hold that Wedgewood was not exempt from FDA inspection under the FDCA, and that issuance of the warrant did not deny Wedgewood procedural due process.  Accordingly, we will affirm the decision of the District Court.

To read the entire decision, click here.

U.S. Pharmcopeial Compounding Expert Committee and Focus Areas

The U.S. Pharmacopeial Convention (USP) has a compounding expert committee with focus areas.  The members and focus areas are listed below.  The committee's work plan can be downloaded here.

2010–2015 Compounding Expert Committee

Focus Areas include: 

 

Human Drug Compounding (Sterile and Nonsterile)

Veterinary Drug Compounding

Radiopharmaceuticals Compounding

Compounding Flavorings

Expert Committee Members

Gigi S. Davidson, B.S. Pharm., DICVP, Chair

Lisa D. Ashworth, B.S. Pharm., R.Ph., Vice Chair

Loyd v. Allen, Ph.D.

Edmund J. Elder, Jr. Ph.D.

Maria do Carmo M Garcez, B.S. Pharm.

Deborah R. Houston, Pharm.D.

Ken Hughes, R.Ph.

Eric S. Kastango, B.S.Pharm., M.B.A.

Patricia C. Kienle, M.P.A.

Keisha D. Lovoi, B.S.Pharm.

Linda F. McElhiney, Pharm.D.

William A. Mixon, M.S.

David W. Newton, Ph.D.

Alan F. Parr, Pharm.D., Ph.D.

Regina F. Peacock, Ph.D.

Robert P. Shrewsbury, Ph.D.

Keith St. John, M.S.

Government Liaisons

Ian F. Deveau, Ph.D.

Edisa Gozun

Martine Hartogenesis, DVM

John W. Metcalfe, Ph.D.

Terrance W. Ocheltree, Ph.D., R.Ph.

Judith McMeekin, Pharm.D.

Yichun Sun, Ph.D

USP Documentary Standards Staff

Shawn Becker, M.S., R.N.

Anthony DeStefano, Ph.D.

Donna Goldberg, M.Ph.

Rick Schnatz, Pharm.D.

Ivonne Zuniga

 

Primary Points of Contact

Rick Schnatz, Pharm.D. (rxs@usp.org)

Jeanne Sun, Pharm.D. (jhs@usp.org)

 

 

Compounding Concerns for Animals Near and Dear

A article by Alice Villalobos, DVM that appears in the Veterinary Practice News, which can read here, makes some very good points about compounding for animals.

First, Villalobos asks:

Competitive pricing, counterfeit drugs, unreliable sources for drugs and the honesty that our profession must maintain present an everyday dilemma. How can veterinarians avoid being tarnished by scandals of adulterated and contaminated food and drugs and still maintain the public’s trust?

Next, Villalobos points out a number of the current issues regarding compounding for animals:

The hundreds of compounding pharmacies nationwide do not use standardized methods or bases for their compounded products. Only a few pharmacies run tests on the stability of their purchased and outsourced compounds.

Some are illegally manufacturing medications under the guise of pharmacy compounding. The field has sprawled into a confusing crossover situation for veterinarians. We have human pharmacists preparing products for animals. If they do not respect and understand the human-animal bond, they might purchase “bargain” bulk or raw chemical preparations made in China and other unreliable sources to save money. Without testing these bargain agents for reliability, stability and contaminants, our patients are at risk.

For instance, potassium bromide, cisapride and diethylstilbestrol and other discontinued or no-longer-approved human drugs can be prepared only from bulk chemicals for veterinary medicine, and they are loosely supervised. We need to protect our veterinary patients from being victimized by this potential hazard. 

Proper Handling

For example, Pergolide for horses is available only through compounding pharmacies. Compounded Pergolide is stable for 30 days and must be kept in a temperature-sensitive environment. Many pharmacies sell Pergolide with a six-month dating, and the product is not stored adequately to ensure its stability.

Finally, Villalobos makes an excellent point, with quotes from Gigi Davidson, RPh, Dipl. ICVP, director of clinical pharmacy services at North Carolina State University, about the Veterinarian ultimately being responsible:

 “Ultimately, the veterinarian is accountable for what happens to the patient.""Veterinarians must realize that even if evidence abounds regarding the safety and efficacy of a compound, they are responsible for determining whether the compound is achieving the desired therapeutic effect,” Dr. Davidson wrote in a recent article for AAHA News.

“Veterinarians should keep track of the results for their patients who have been prescribed compounds and make sure they know what exactly is going into each prescription.” 

Davidson cited the case of a canine patient treated with pyridostigmine (Mestinon) solution for myasthenia gravis at the N.C. State College of Veterinary Medicine's teaching hospital. The dog was doing well on the treatment but returned several months later weak and unable to stand.

"Apparently the owner had taken her prescription for pyridostigmine solution to a compounding pharmacy and the well-intentioned pharmacist had offered to compound a more dog-friendly flavor of the pyridostigmine," Davidson said. "Unfortunately, the pharmacist included methylcellulose in the vehicle which completely bound the pyridostigmine, making it unavailable for absorption. Luckily, we realized the mistake before the dog was euthanized."

Idaho Board of Pharmacy Plans to Adopt Sterile Product Compounding Rules

The Idaho Board of Pharmacy looks to adopt sterile product compounding rules in 2012 as stated in its strategic plan found here.  Part of that plan states:

The Board envisions regulating the practice of compounding pharmacy.  This practice has traditionally been regulated by the United States Food and Drug Administration (FDA), however, the FDA’s authority has been challenged in court recently, leaving such regulation to the states.  The Board envisions promulgating sterile product compounding rules in 2012 and additional compounding rules in 2013, reviewing such rules annually.    

New Legislation in Virginia Dealing With Compounding

New Legislation in Virginia Dealing with Compounding:

VIRGINIA ACTS OF ASSEMBLY -- 2012 SESSION
CHAPTER 173
An Act to amend and reenact § 54.1-3410.2 of the Code of Virginia, relating to pharmacists' authority
to compound.
[H 733]
Approved March 8, 2012
Be it enacted by the General Assembly of Virginia:
1. That § 54.1-3410.2 of the Code of Virginia is amended and reenacted as follows:
§ 54.1-3410.2. Compounding; pharmacists' authority to compound under certain conditions; labeling
and record maintenance requirements.
A. A pharmacist may engage in compounding of drug products when the dispensing of such
compounded products is (i) pursuant to valid prescriptions for specific patients and (ii) consistent with the provisions of § 54.1-3303 relating to the issuance of prescriptions and the dispensing of drugs.
Pharmacists shall label all compounded drug products that are dispensed pursuant to a prescription inaccordance with this chapter and the Board's regulations, and shall include on the labeling an appropriate beyond-use date as determined by the pharmacist in compliance with USP-NF standards for pharmacy compounding.
B. A pharmacist may also engage in compounding of drug products in anticipation of receipt of
prescriptions based on a routine, regularly observed prescribing pattern.
Pharmacists shall label all products compounded prior to dispensing with (i) the name and strength of the compounded medication or a list of the active ingredients and strengths; (ii) the pharmacy's assigned control number that corresponds with the compounding record; (iii) an appropriate beyond-use date as determined by the pharmacist in compliance with USP-NF standards for pharmacy compounding; and
(iv) the quantity.
C. In accordance with the conditions set forth in subsections A and B, pharmacists shall not
distribute compounded drug products for subsequent distribution or sale to other persons or to
commercial entities, including distribution to pharmacies or other entities under common ownership or control with the facility in which such compounding takes place.
A pharmacist may, however, deliver compounded products dispensed pursuant to valid prescriptions
to alternate delivery locations pursuant to § 54.1-3420.2.
A pharmacist may also provide compounded products to practitioners of medicine, osteopathy,
podiatry, dentistry, or veterinary medicine to administer to their patients in the course of their
professional practice, either personally or under their direct and immediate supervision.
Pharmacists shall label all compounded products distributed to practitioners for administration to their patients with (i) the statement "For Administering in Prescriber Practice Location Only"; (ii) the name and strength of the compounded medication or list of the active ingredients and strengths; (iii) the facility's control number; (iv) an appropriate beyond-use date as determined by the pharmacist in compliance with USP-NF standards for pharmacy compounding; and (v) quantity.
D. Pharmacists shall personally perform or personally supervise the compounding process, which
shall include a final check for accuracy and conformity to the formula of the product being prepared,
correct ingredients and calculations, accurate and precise measurements, appropriate conditions and
procedures, and appearance of the final product.
E. Pharmacists shall ensure compliance with USP-NF standards for both sterile and non-sterile
compounding.
F. Pharmacists may use bulk drug substances in compounding when such bulk drug substances:
1. Comply with the standards of an applicable United States Pharmacopoeia or National Formulary
monograph, if such monograph exists, and the United States Pharmacopoeia chapter on pharmacy
compounding; or are drug substances that are components of drugs approved by the FDA for use in the United States; or are otherwise approved by the FDA;
2. Are manufactured by an establishment that is registered by the FDA; or
3. Are distributed by a licensed wholesale distributor or registered nonresident wholesale distributor,
or are distributed by a supplier otherwise approved by the FDA to distribute bulk drug substances if the pharmacist can establish purity and safety by reasonable means, such as lot analysis, manufacturer reputation, or reliability of the source.
G. Pharmacists may compound using ingredients that are not considered drug products in accordance with the USP-NF standards and guidance on pharmacy compounding.
H. Pharmacists shall not engage in the following:
1. The compounding for human use of a drug product that has been withdrawn or removed from the
market by the FDA because such drug product or a component of such drug product has been found to be unsafe. However, this prohibition shall be limited to the scope of the FDA withdrawal; or
2. The regular compounding or the compounding of inordinate amounts of any drug products that are essentially copies of commercially available drug products. However, this prohibition shall not include
(i) the compounding of any commercially available product when there is a change in the product
ordered by the prescriber for an individual patient, (ii) the compounding of a commercially
manufactured drug only during times when the product is not available from the manufacturer or
supplier, or (iii) the compounding of a commercially manufactured drug whose manufacturer has
notified the FDA that the drug is unavailable due to a current drug shortage, (iv) the compounding of a commercially manufactured drug when the prescriber has indicated in the oral or written prescription for an individual patient that there is an emergent need for a drug that is not readily available within the time medically necessary, or (v) the mixing of two or more commercially available products regardless of whether the end product is a commercially available product.
I. Pharmacists shall maintain records of all compounded drug products as part of the prescription,
formula record, formula book, or other log or record. Records may be maintained electronically,
manually, in a combination of both, or by any other readily retrievable method.
1. In addition to other requirements for prescription records, records for products compounded
pursuant to a prescription order for a single patient where only manufacturers' finished products are used as components shall include the name and quantity of all components, the date of compounding and dispensing, the prescription number or other identifier of the prescription order, the total quantity of finished product, the signature or initials of the pharmacist or pharmacy technician performing the compounding, and the signature or initials of the pharmacist responsible for supervising the pharmacy technician and verifying the accuracy and integrity of compounded products.
2. In addition to the requirements of subdivision I 1, records for products compounded in bulk or
batch in advance of dispensing or when bulk drug substances are used shall include: the generic name and the name of the manufacturer of each component or the brand name of each component; the manufacturer's lot number and expiration date for each component or when the original manufacturer's lot number and expiration date are unknown, the source of acquisition of the component; the assigned lot number if subdivided, the unit or package size and the number of units or packages prepared; and the beyond-use date. The criteria for establishing the beyond-use date shall be available for inspection by the Board.
3. A complete compounding formula listing all procedures, necessary equipment, necessary
environmental considerations, and other factors in detail shall be maintained where such instructions are necessary to replicate a compounded product or where the compounding is difficult or complex and must be done by a certain process in order to ensure the integrity of the finished product.
4. A formal written quality assurance plan shall be maintained that describes specific monitoring and
evaluation of compounding activities in accordance with USP-NF standards. Records shall be maintained showing compliance with monitoring and evaluation requirements of the plan to include training and initial and periodic competence assessment of personnel involved in compounding, monitoring of environmental controls and equipment calibration, and any end-product testing, if applicable.
J. Practitioners who may lawfully compound drugs for administering or dispensing to their own
patients pursuant to §§ 54.1-3301, 54.1-3304, and 54.1-3304.1 shall comply with all provisions of this section and the relevant Board regulations.

Another Article Suggest that the FDA May Start Inspecting More Compounding Pharmacies

Another article entitled Report: Compounding Regulatory Issues Come to Light After 'Urgent' Recall by Alexander Gaffney  suggest that the FDA may start inspecting more compounding pharmacies.  The article states:

Not all pharmacists have the same level of skills and equipment,” said Rear Admiral Steven Galson, deputy director of the Center for Drug Evaluation and Research at FDA and the US’s acting surgeon general. “In some cases, compounders may lack sufficient controls—equipment, training, testing, or facilities—to ensure product quality or to compound complex products such as sterile or modified release drugs.”

Because the majority compounds are made-to-order and exist in small quantities, many current good manufacturing practices such as lot and batch testing are impossible. “The quality of the drugs that these pharmacists compound is uncertain and these drugs pose potential risks to the patients who take them,” concluded Galson.

However, large-volume suppliers such as Franck’s are frequently making batches of products in amounts suitable for quality testing, creating tensions between FDA and the compounders, report The Star-Banner.

In response, FDA is starting to leverage its oversight authority towards companies “whose activities raise the kinds of concerns normally associated with a drug manufacturer and whose compounding practices result in significant violations of” The Federal Food, Drug and Cosmetic Act, said Galston in previous testimony before Congress.

To read the entitle article, click here.

House Passes FDA Reform Act of 2012

The U.S. House of Representatives passed H.R. 5651, the FDA Reform Act of 2012, as amended, on May 30th by a vote of 387-5. The U.S. Senate had already passed its version of the bill. See previous post and here. This House Report explains the bill’s history and includes a section-by-section analysis. Both bills reauthorize and amend old (PDUFA and MDUFA) and establish new (GDUFA and BsUFA) user fee statutes, permanently reauthorize the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act.  Next, a conference committee will reconcile differences between the House and Sentate bills. The Senate bill contains provisions, not included in the House bill, such as provisions on drug track and trace, Risk Evaluation and Mitigation Strategies, and changes to the Controlled Substances Act.  The House bill contains provisions on generic drug 180-day exclusivity forfeiture, citizen petitions, and drug shortages not included in the Senate bill. The Congressional Research Service has a side-by-side comparison of current law, S. 3187 and H.R. 5651. After the committee reaches a compromise on differences in the House and Senate bill, the legislation will be sent to the President for his signature.  This is expected to happen by the end of June or early July.

U.S. Senate passed the Food and Drug Administration Safety and Innovation Act

Senate Easily Passes FDA User Fee Bill, Reconciliation with House Version Looms

article found here.

by McDermott Will & Emery on 5/30/2012

authors: James S. Cohen and Michael W. Ryan]
In a nearly unanimous decision, the U.S. Senate passed the Food and Drug Administration Safety and Innovation Act on May 24, 2012. The bill would reauthorize the drug and device user fee programs and, for the first time, allow the Food and Drug Administration (FDA) to collect user fees from generic drug and biosimilar manufacturers. The bill is expected to raise $6.4 billion over the next five years to cover a portion of the costs of the FDA’s review of medical product marketing applications. In addition, the bill would implement a number of changes to the FDA’s review and oversight of drugs, devices and biologicals. The House of Representatives is expected to take up consideration of a similar House bill this week.
After months of negotiations, on May 24, 2012, the U.S. Senate passed the Food and Drug Administration Safety and Innovation Act, a bipartisan bill that would reauthorize the Food and Drug Administration (FDA) drug and medical device “user fee” programs and, for the first time, allow the agency to collect user fees from generic drug and biosimilar manufacturers. The bill, which passed by a vote of 96-1, is expected to raise $6.4 billion for the FDA over the next five years, which will be used to cover a portion of the costs associated with the agency’s review of marketing applications for the above-referenced products.
In addition to the user fee authorizations/reauthorizations, the bill proposes a number of changes to the agency’s oversight of drugs, medical devices and biologicals. Specifically, the bill would:

• Allow the FDA to change the classification of a device by administrative order. Such changes—which are currently made only through regulation—must be proposed by the Director of the Center for Devices and Radiological Health (CDRH) and issued by the Commissioner.
• Expressly require the FDA to extend its “Sentinel” post-market risk identification and analysis system to include medical devices. To ensure effective implementation, the FDA would be required to engage outside stakeholders through a public hearing, advisory committee meeting, public docket or similar public measure.
• Require the FDA to issue proposed regulations establishing a unique device identification (UDI) system by December 31, 2012. The FDA would be required to finalize the regulations within six months of the close of the comment period on the proposed rule, and to implement the regulations for implantable, life-saving and life-sustaining devices within two years of the UDI regulations being finalized. The legislation aims to speed up the process of implementing UDI regulations, which have been under development at the FDA for some time.
• For medical devices, require the FDA to provide a “substantive summary of the scientific and regulatory rationale” for decisions to deny clearance of a premarket clearance submission under section 510(k) of the Federal Food, Drug, and Cosmetic Act (FDCA), to deny approval of a premarket approval application or to disapprove of an investigational device exemption application to conduct a clinical trial. In addition, applicants who receive a negative response on one of the above-referenced applications will be permitted to request a supervisory review of the decision to deny clearance or approval (i.e., review by an individual “at the organizational level above the organization level at which the decision to deny the clearance of the report or approval of the application is made”) within 30 days of receiving such response.
• Permit the FDA to classify a new medical device without predicates directly through de novo review into Class I or II without first requiring a “not substantially equivalent” determination under the 510(k) clearance process. The FDA may refuse to consider such a request, however, if it identifies a legally marketed device that could provide a reasonable basis for review of a substantially equivalent determination; if it determines the device is not of low-moderate risk; or if it determines “general controls” would be inadequate to control risk and “special controls” to mitigate risks cannot be developed for the proposed device.
• Prohibit the FDA from releasing final guidance on medical mobile applications until the FDA drafts a report that “contains a proposed strategy and recommendations on an appropriate, risk-based regulatory framework pertaining to medical device regulation and health information technology software, including mobile applications,” and convenes a working group to provide input on the contents of the report. The bill would require the FDA to submit this report to Congress no later than 18 months after the date of the bill’s enactment. The FDA had issued a draft guidance establishing a risk-based model for how it would regulate mobile medical applications, and the legislation would require the FDA to issue a report to explain the FDA’s approach after convening a working group that would include a variety of external stakeholders. While many application developers welcome a comprehensive, consistent and risk-based approach and the involvement of external stakeholders in the development of mobile medical application policy, there is some concern on the part of the developers (and the FDA) about a process that would delay providing the industry with regulatory clarity on the use of innovative and important medical mobile applications.
• Require the FDA to withdraw its draft “Guidance for Industry and Staff – 510(k) Device Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device.” The draft guidance, which was released in July 2011, has been heavily criticized by the device industry, with one reported estimate that the new guidance will increase the number of devices subject to the 510(k) clearance process anywhere from 300 percent to 500 percent. Consistent with this concern, during a March 2012 congressional hearing, CDRH Director, Dr. Jeffrey Shuren, noted that implementation of the draft guidance may lead to some unintended consequences and indicated the FDA intends to rework the guidance document. In addition to requiring the withdrawal of the draft guidance, the bill would require the FDA to ensure affected stakeholders are provided with an opportunity to comment on any future guidance before the document is made final.
• Expand the information required of domestic and foreign facilities that manufacture, prepare, propagate, compound or process FDA-regulated products. Domestic and foreign drug establishments would be required to report their unique facility identifier, a point of contact’s e-mail address and information about each drug importer that takes physical possession of the drug (among other information). Foreign device facilities would be required to submit their name and place of business, the name of the U.S. agent for the facility, place of business and the name of each person who imports or offers to import such device into the United States. The bill authorizes the FDA to “specify the unique facility identifier system.”
• Require the FDA to carry out drug facility inspections according to a risk-based schedule. Factors that the FDA would be required to consider in assessing risk include the compliance history of the establishment, the record, history and nature of recalls linked to the establishment, and the inherent risk associated with the drug manufactured, prepared, propagated, compounded or processed at the establishment, among others.
• Allow the FDA to require establishments and wholesale drug distributors to notify the FDA of “substantial loss or theft” of drug, or if a drug has been or is being counterfeited and is in commerce in the United States or offered for import into the United States. These notifications must be made “in a reasonable time, in such reasonable manner, and by such reasonable means as the [FDA] may require.”
• Enhance penalties for knowingly and intentionally adulterating, counterfeiting and/or forging drugs. An individual who knowingly and intentionally adulterates a drug in a manner that has reasonable probability of causing serious adverse health consequences or death shall be imprisoned for a maximum of 20 years and/or fined up to $1 million. Individuals who are convicted of knowingly and intentionally counterfeiting or forging drugs may also be imprisoned for up to 20 years and/or fined up to $4 million. The penalties for either violation are currently capped at up to three years of imprisonment and/or a $10,000 fine.
• Extend market exclusivity for certain new antibiotics intended to treat serious or life-threatening infections by five years. Conditions identified as potentially serious or life-threatening include conditions caused by resistant gram-positive pathogens, multi-drug resistant gram negative bacteria, multi-drug resistant tuberculosis and C. difficile. Products intended to treat these conditions are also eligible for priority marketing application review.
• Require manufacturers of certain drugs to notify the FDA at least six months before taking action that would result in a permanent discontinuance of the manufacture of a drug or an interruption of the manufacture of a drug that could lead to a meaningful disruption in overall drug supply. This requirement would apply to manufacturers of drugs that are life-supporting, life-sustaining, intended for use in the prevention of a debilitating disease or condition, a sterile injectable product, or used in emergency medical care or during surgery (excluding products that are radiopharmaceuticals, human tissue replaced by a recombinant product, a product derived from human plasma or any other product designated by the FDA).
• Require the FDA to consider, before the issuance of enforcement action, the effect of such action on the availability of certain drugs. While the FDA often considers potential shortages when determining the extent or nature of enforcement action (e.g., in injunction actions), particularly for vaccines or sole source products, this provision would affirmatively require the FDA to consider the effect of any enforcement action or issuance of a warning letter that the FDA determines could “reasonably be anticipated to lead to a meaningful disruption” in the supply of certain drugs, e.g., drugs that are life-supporting, life-sustaining, intended for use in the treatment of a debilitating disease or condition, a sterile injectable product, or used in emergency medical care or during surgery (excluding products that are radiopharmaceuticals, human tissue replaced by a recombinant product, a product derived from human plasma or any other product designated by the FDA), in the United States. The FDA would be required to consult with an office of the FDA with expertise in drug shortages in making this determination.
• Require the FDA to issue guidance describing its policy on the promotion of FDA-regulated products on the internet. The guidance must be issued within two years after the date of enactment of the legislation. This provision would speed up the FDA’s development and issuance of guidance, and provide more clarity to the industry, on internet-related advertising, including through social media.
• Provides that the elements to assure safe use in a risk evaluation and management strategy (REMS) may not be used to prohibit access to a drug or biological by a generic drug or biosimilar manufacturer. The bill states that as part of each REMS program, the FDA shall require that the holder of an application for an innovator drug or biological not restrict the resale of the drug or biological to an eligible generic drug or biosimilar developer for the purpose of testing in support of a generic or biosimilar marketing application if the manufacturer of the innovator product receives written notice from the FDA.
• Require the FDA to develop and implement strategies to solicit the views and perspectives of patients during product development and regulatory discussions. The bill identifies “fostering participation of a patient representative” to participate in agency meetings with clinical trial sponsors and investigators, and “exploring means to identify patient representatives who do not have any, or have minimal financial interest in the medical products industry” as methods for the FDA to facilitate public participation. This provision is consistent with developments in personalized medicine and risk-benefit analysis reforms to more expressly include patient views and patient risk tolerance in the review of data in support of marketing applications.

The Senate bill is also notable for its exclusion of several widely publicized proposed provisions, including proposals to allow United States citizens to import drugs from Canadian pharmacies; to revoke exclusive marketing rights from manufacturers found to be at fault for violations of the FDCA, the False Claims Act (e.g., off-label promotion) or the Anti-kickback Statute (among others); to discourage so-called “pay for delay” patent settlements that are purported to delay generic drugs from entering the market; and to limit enforcement relating to dietary supplements.

With the Senate’s vote, the Food and Drug Administration Safety and Innovation Act now moves to the House of Representatives, which has been working on its own version of a user fee bill. The House bill, which was recently reported from the House Energy and Commerce Committee, differs in some respects from the Senate bill described above, and thus, the chambers will likely iron out any differences between the two bills through a formal or informal “reconciliation process” prior to submitting a final bill for President Obama’s signature. Notwithstanding this remaining process, members of both chambers of Congress are aiming to have a final bill on the President’s desk by the first week of July—well before the FDA’s current authorization to charge user fees expires on September 30, 2012.

Implications

In a surprising show of bipartisan cooperation, the Senate’s nearly unanimous approval of the Food and Drug Administration Safety and Innovation Act is an important step toward ensuring the FDA has the financial resources it needs to continue to review marketing applications for FDA-regulated products. Because the majority of the funding required to review marketing applications comes from user fees, the agency’s inability to charge such fees would significantly inhibit its ability to review applications in a timely manner.

The nearly unanimous passage of the Senate bill and the absence of some of the more controversial provisions that had been under discussion, or proposed as amendments, signifies congressional and administration recognition of the importance of prompt review and approval of innovative and life-saving medical products for patients. In addition, the bipartisan passage of the bill represents acknowledgment that speedier review and approval of medical products provides incentive for investments in important medical research.

The full House of Representatives is expected to take up consideration of the House bill this week (week of May 28, 2012).