While reviewing the NDA, the FDA will consider three larger questions:

• Is this drug safe and effective for its proposed use?  Do the benefits of this drug outweigh its risks?

• Is the drug label appropriate and does it contain the proper information?

• Has the manufacturer instituted sufficient controls to maintain and ensure the drug’s quality, strength and purity?

In particular, FDA scientific and regulatory staff will prepare several assessments covering a wide range of medical, clinical and risk mitigation topics relevant to the applicant drug.  The law requires that the FDA approve only after it has received “substantial evidence” of a drug’s safety and effectiveness.  However, the FDA has flexibility in determining what it requires as evidence.  It can rely on studies solely from those of the manufacturer itself or at its discretion include independent studies and evaluations in its review.  Sometimes, the FDA will even convene an advisory panel of outside experts to review data, although the FDA is not bound by their recommendations.  Once the FDA makes a final determination, the agency will send out either an approval letter or a “complete response letter” detailing where the NDA fell short of approval.

In 1984, Congress passed the “Hatch-Waxman Act” which established an abbreviated pathway for so-called “generic” drugs.  Specifically, it allows manufacturer sponsors to submit an “Abbreviated New Drug Application” or ANDA (as opposed to a full NDA).  The ANDA allows the manufacturer to bypass the replication and submission of animal and clinical trial data – instead relying on the data submitted by the manufacturer sponsor from the original NDA.  The ANDA must only demonstrate that the generic equivalent is pharmaceutically the same as the original “brand name” product submitted under the NDA.

Special Regulatory “Fast Tracking”

Drugs that address “unmet needs” or “serious conditions” or address other criteria associated with “improved public health”, the FDA uses several formal mechanisms to expedite the drug development and review process. Specifically:

• Fast Track and Breakthrough Products: Fast tracking does not necessarily mean a reduction in the data submitted by the manufacturer, as much as it compresses the time the agency takes to convene experts and meet to decide a drug’s NDA.
• Accelerated Approval/Animal Efficacy Approval: If a drug is deemed necessary, but human trials are not ethical or feasible, approval of a drug may be based on animal control studies alone.
• Priority Review: Again, this does not impact the data which must be submitted, but compresses the timeline for review by the FDA itself.

Over-the-Counter Drug Approval

Over-the-Counter (OTC) drugs are sold directly to consumers without a prescription.  Like prescription medications, OTCs are regulationed by the FDA and treat many common ailments such as pain, fever, cough/cold and upset stomach.  Because OTC drugs are taken outside of the supervision of a physician, they generally require a wider margin of safety for their routine use and labeling that ordinary consumers can understand.  OTC drugs may be manufactured and sold without going through a standard NDA process.  An OTC drug must only “conform” to an OTC monograph – a regulatory standard for the labeling of ingredients within the product.

Overview of the FDA Medical Device Approval Process

As with drugs, many medical devices must be reviewed bny the FDA prior to their being legally marketable in the United States.  However, not all devices receive the same level of review and as American patients are finding out, lack of review and scrutiny can result in painful consequences and a lifetime of suffering.

The FDA’s Center for Devices and Radiological Health (CDRH) bears primary responsibility for medical device review.  Under U.S. law, all medical device manufacturers must register their manufacturing facilities and list their devices with the FDA.  The FDA will then classify those devices on the basis of the risk they pose to patients: low; moderate or high.  Moderate or high-risk devices must seek “pre-market approval” from the FDA with an application that assures the FDA of the device’s safety and effectiveness.

Standard Pre-Market Approval

The ordinary Pre-Market Approval (PMA) process is tightly controlled by the FDA.  A PMA application is based upon the FDA’s determination that the manufacturer’s application contains sufficient valid scientific evidence to provide a “reasonable assurance” that the device is safe and effective for its intended use.  Approval of a PMA requires that the FDA review copious clinical and scientific data about the device and how it will perform in human subjects.  Additionally, the FDA may convene advisory panels to review and make recommendations based upon the submitted data.  The approval timeframe for a full PMA can take months or years.  In 2015, 98% of PMAs accepted for filing were approved by the FDA.

510(K) Notification

In contrast to the rigorous evaluation and application protocols within the PMA application process, the FDA will also allow some manufacturers of “moderate risk” devices to bypass the PMA altogether and fastlane products onto the market with comparatively little scrutiny.  Using what is termed as the “510(k) Notification” or “510(k) Approval” pathway, manufacturers can submit new products which can trace their lineage back to a pre-approved product with only “minor” technical, design or performance changes – also known as “substantial equivalence”.  Many 510(k) applicants trace their “substantial equivalence” lineage back to products which were approved by various state regulatory agencies before the FDA was given regulatory authority in the 1970s.

Between 1996 and 2009, more than 80% of the devices cleared by the FDA posed a “moderate risk” (Class II) and the General Accounting Office (GAO) found that 25% of the Class II devices implanted between 2003 and 2007 were either “implantable, life sustaining or presented a significant risk to the health safety and welfare of the patient”.  It is worth noting that the FDA cleared 90% of 510(k) submissions reviewed during this same time period.

In 2008, an orthopaedic device made by ReGen, a New Jersey company, was cleared for market using the 510(k) process.  In April 2009, the then-Acting FDA Commissioner initiated an internal review of the decision to clear the ReGen MenaFlex device.  The FDA report that ensued provided a list of 22 instances wherein the FDA did not follow established processes, procedures or practices.  The final report chalked up many of the issues at the FDA to broad “confusion” about the legal standards imposed by the 510(k) process.

Criticism of the 510(k) Process

At the behest of the FDA, the Institute of Medicine (IOM) studied the 510(k) process and produced a significant report with many suggestions and criticisms of the process.  Overall, the IOM recommended that the 510(k) process be “replaced with an integrated premarket and postmarket regulatory framework that effectively provides a reasonable assurance of safety and effectiveness throughout the device life cycle”.

It is worth noting that the 510(k) process has not been duplicated elsewhere (in contrast to the FDA’s drug application system – which has been replicated in many other countries).  Other countries continue to tightly regulate medical devices and do not rely on “substantial equivalence” to a previously approved device for market clearance.