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Comparative Assessment for Medications and Devices: Applesand Oranges?

Scott Ramsey, MD, PhD

University of Washington, Fred Hutchinson Cancer Research Center, Seattle,WA, USA

Keywords: 510(k), clinical trials, premarket approval, premarket notification.

Introduction

Over the past two decades, there have been multiple attempts bygovernment to fund comparative effectiveness research (CER) inthe US. Unfortunately, these efforts have been stymied, typicallyby Congress refusing to commit the scale of funding necessary toaddress the magnitude of clinical problems for which such infor-

mation would influence practice. As a result, to date, the drugand device regulatory approval system has been the primarydriver of the type of evidence that is generated to support aproduct launch. The great majority of evidence generated forregulatory approval could not be construed as comparative effec-tiveness research.

In an unprecedented move, new legislation passed by Con-gress known as the American Recovery and Reinvestment Act(ARRA) that was aimed at overcoming the economic downturn,includes $1.1 billion dollars to support CER in the US; the size ofthis budget is orders of magnitude more than has ever beencommitted to this field. These funds are being distributed viathree main routes: the Office of the Secretary of Health andHuman Services, the director of the National Institutes of Health,and the Agency for Healthcare Research and Quality.

Because of the ongoing debate around what constituted com-parative effectiveness research, the ARRA legislation specificallycalled on the Institute of Medicine (IOM) to define comparativeeffectiveness and to set CER priorities. Ironically, comparativeeffectiveness research funds were already flowing out of theNational Institutes of Health (NIH) before the IOM published itsdefinition of CER (subsequently published August 4, 2009), orthe IOM priority areas established. The IOM Committeeworking definition of CER is given below:

CER is the generation and synthesis of evidence that com-pares the benefits and harms of alternative methods toprevent, diagnose, treat, and monitor a clinical condition, orto improve the delivery of care. The purpose of CER is toassist consumers, clinicians, purchasers, and policymakers to

make informed decisions that will improve health care atboth the individual and population levels (adapted from [1])

The NIH had set its own priorities and released more than$200 million dollars to fund several hundred research programs.

In light of the debate about what CER was, it is noteworthythat the IOM definition of CER includes consumers and purchas-

ers as beneficiaries of the research, implying that costs or cost-effectiveness are valid metrics of comparison.

Regulation of Drugs and Devices in the USThe process of regulation that brings new drugs and devices tomarket illustrates the reason why many researchers and policy-

makers felt that comparative effectiveness research was needed.One of the first decisions the Food and Drug Administration(FDA) makes about a new technology is whether it is a drug ora device as defined in the Food and Drug and Cosmetic Act(Table 1). The regulatory requirements set by the FDA are quitedifferent for these categories. After determining whether aproduct is a drug or device, meeting these requirements is key toaccessing the health-care market.

It is important to note that neither of these definitionsrequires that a drug or device show equivalence or superiority tobest alternative care. Indeed, most products come to market withstudies comparing them to placebo or best supportive care (i.e.,care that does not intend to cure the condition).

Drug Labeling and Promotion

The drug label (stated indication) drives the use of drugs anddevices in the US; it is limited to proven efficacy and safety.Although drugs may be prescribed off-label, by law, the drug ordevice cannot be promoted beyond the bounds of what is on thelabel.

Drug Development

Drug development is a very long and costly process that startsfrom basic research, preclinical and the investigational new drugapplication, and goes from Phase One to Phase Three (oftencalled pivotal) clinical trials. Phase One clinical trials are thefirst human trials of a new drug. They typically involve testingthe drug in a small number of healthy individuals to determine

whether it is metabolized as expected, and what side effectsoccur. Phase Two trials are then conducted to test drug efficacy.They typically involve a small number of patients and are alsooften designed to establish an appropriate dosage, as well as tocontinue to build the safety profile. Phase Three trials are largecontrolled trials that assess safety and efficacy in the generalpatient population. They typically involve one or more largecohorts of patients, with international representation. The com-parator may be a placebo, an active comparator, or currentstandard of care.

If a drug shows significant clinical improvement in outcomesand reasonable safety in two double-blind, controlled studies, theFDA may grant approval to market the drug, after which the

Address correspondence to: Scott Ramsey, University of Washington,

Member, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-

1024, USA. E-mail: sramsey@fhcrc.org

10.1111/j.1524-4733.2010.00748.x

Scott Ramsey has no conflicts to declare.

Volume 13 Supplement 1 2010

V A L U E I N H E A L T H

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product is launched. A typical time horizon to get from conceptto approval is 8 to 10 years, although it may be longer. Theestimated cost of bringing a new chemical entity to the market,including the legislated fee for the FDA review, is in the order ofabout $800 million dollars [2].

Limitations of the Regulatory Process for DrugsTrial-based evaluations of safety and efficacy have several limi-

tations for clinicians and other decision-makers. First, the trialbased populations typically represents a select patient populationrather than patients in the real world; as such, the results maynot be generalizable. Second, as noted above, the comparator istypically not the best alternative treatment. Placebo or theweakest alternatives tend to be selected, rather than standard ofcare. Other limitations are that study endpoints are typicallyshort-term, and the studies are often underpowered to determinepopulation-wide safety endpoints.

Device Development

The FDA classifies devices that are submitted to them forapproval into three classes:

1. Class I: Low-risk devices; e.g., band-aids, crutches. Thesetypes of devices are subject to general controls with lowstringency.

2. Class II: Medium-risk devices; e.g., syringes. These types ofdevices are subject to general controls plus additionalspecial controls that are often related to manufacturingprocesses (quality control).

3. Class III: High-risk devices; e.g., drug-eluting stents. Thesetypes of devices are subject to general controls and a systemof premarket approval (PMA) that requires evidencegeneration.

There are two routes to getting a device approved through theFDA; premarket notification or 510(k), and premarket approval(PMA). The vast majority of devices get approved through the

510(k) process. PMA only applies to Class III devices. If it ispermitted by the FDA, device manufacturers much prefer the510(k) route, as it simply requires proving substantial equiva-

lence to a currently marked device, and therefore is much lesscostly and faster than PMA (Table 2).

Premarket Notification, 510 (k)The 510(k) process requires the manufacturer to demonstratethat the new device is substantially equivalent to an existingdevice that is already marketed in the US, with substantial

equivalence being defined as meaning that the device is as safeand as effective as the existing device. It is worth noting thatsetting the regulatory standard at proving that a new device is asgood as existing technology creates somewhat of a conundrumfor purchasers and clinicians, as after gaining approval, themanufacturer may market their device as the best new thing.

PMAThis process applies when the FDA decides that the technology isnot substantially equivalent to an existing technology because itis a novel entity; as such, it is considered to be of high-risk. Inthese cases, the manufacturer must prove reasonable assurance ofsafety and effectiveness. As shown in Table 2, the standard fee forPMA is much higher and the review time much longer than for

510(k). However, the major expense for the manufacturer is incases where the FDA requires a prospective study (although notnecessarily controlled) that demonstrate the safety and effective-ness of the device.

Limitations of the Regulatory Process for DevicesThere are a number of limitations of the regulatory process fordevices. First, there is currently no requirement by the FDA forrandomized controlled trials of devices versus best alternativecare. In fact, the vast majority go through the 510(k) process,which requires a comparison to an older device, but no trial ofany sort. A second very important limitation is that operator skillis not part of the regulatory process. Evidence suggests thatvariations in operator skill can lead to significantly differentpatient outcomes. As a well-described example, perioperativemortality associated with lung volume reduction surgery withbovine pericardium (the device) was reduced from around1215% prior to the pivotal trial of this procedure to 5% whenthe procedure was carried out by skilled operators. However,bovine pericardium obtained FDA device approval withoutattention to the role of operator competence or its ultimate use incare. This example draws attention to the lack of focus ondefinitive outcomes and patient oriented outcomes.

Closing Remarks

The FDA applies very different processes to evaluating drugs anddevices. Although the regulatory process for drugs stimulates theproduction of good quality evidence of whether thedrug improves

outcomes fora particular condition, this may imply that it is betterthan best alternative care or that the results from the clinical trialpopulation are generalizable to the real world. Getting drugs

Table 1 Food and Drug Administration working definitions of drugs and

devices

Drugs Articles that are recognized in the Official United StatesPharmacopoeia, or Official National Formulary, or any supplementto any of them; they are articles (other than food) that areintended for use in the diagnosis, cure, mitigation, treatment, orprevention of disease in man or other animals that are intendedto affect the structure or any function of the body.

Devices Articles used in the diagnosis, cure, mitigation, treatment orprevention of disease or medical condition that affect thestructure or function of the body, but that do not achieve theirintended effect through chemical reaction or metabolism.

Table 2 Regulatory approval processes for devices

Premarket notification 510(k) Premarket approval

Standard fees $3,693 $200,725Small business fee $1,847 ($100 million in gross receipts or sales) $30 million in gross receipts or sales - fee is waived*

$100 million in gross receipts or sales - $50,181*Review time 90% completed within 90 days Average of 335 days

*For first application.

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from discovery to market takes years or even decades. The regu-latory process for devices, on the other hand, is usually muchfaster. Because controlled clinical trials are rare for devices, mostdevices come to market with evidence that falls far short of drugs.

The FDAs approach to evaluating and regulating drugs andmedical devices is dictated by statute. Changes in its approach forevaluating new medical devicesfor example, to fit a compara-

tive effectiveness frameworkwould require federal legislation.Because of the uncertainty it would create for the drug and deviceindustries, wholesale adjustments to the FDAs current process ofevaluating medical devices is highly unlikely in the foreseeablefuture. Therefore, one can expect that the bulk of CER willcontinue to be conducted on drugs and devices that have alreadybeen approved for marketing. Conducting CER outside of theFDA regulatory structure does have the advantage of allowingfor novel study designs and comparisons that could addressimportant questions in an efficient and potentially timely manner.

On moving forward, we should have great optimism thatthe new CER funding offers a unique opportunity to improvethe knowledge base for medications and medical devices. Firstand foremost, it is hoped that CER improves patient care. It isalso hoped that the information will help control health-carecosts.

Source of financial support: Oxford Outcomes, the National Pharmaceu-

tical Council, and Shire Pharmaceuticals.

References

1 Sox HC, Greenfield S. Comparative effectiveness research: a reportfrom theInstitute of medicine. Ann Intern Med 2009;151:2035.

2 DiMasi JA, Hansen RW, Grabowski HG, Lasagna L. Cost ofinnovation in the pharmaceutical industry. J Health Econ 1991;10:10742.

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