# Presentation: 399617

## Genetic Testing for Rare Diseases:  A Payor Perspective   

**Moe Mellion, MD**
**Associate Medical Director**
**Margaret Piper, PhD, MPH**
**Technology Evaluation Center**
**Blue Cross and Blue Shield Association**

## Blue Cross and Blue Shield Association (BCBSA)

***= national federation******	****** of independent, locally operated Blue Cross and Blue Shield Plans***

## Blue Cross and Blue Shield Association (BCBSA)

**Activities:****	**
**	****	****Performance standards for plans**
**	****	****Outreach and Education:**
- 			Patients and Providers**	**
**	****	****Legislative/Regulatory Representation**
**	****	****Research**
**	****	****BCBSHealthIssues.com**

## When is a rare disease a “rare” disease? 

##  Orphan Drug Act :	Rare disease affects <200,000	 6,000 rare diseases

**Logical absurdity:**
**	****	****1.2 billion cases **
**	****	****>4 cases per American**
**NIH Office of Rare Diseases:  **
**	****	****25 million cases**

## Orphan Drug Act 1988 Amendmentsfor devices, including genetic tests

**Rare disease =  "any disease or condition that occurs so infrequently in the United States that there is no reasonable expectation that a medical device...will be developed without [financial] assistance." **

## Alternative definition of rare disease:

**FDA Humanitarian Device Exemption**
**<4,000 cases in U.S.**
**Premarketing evidence of effectiveness waived**
- 	(Safe Medical Devices Act of 1990)

## What are important issues for BCBS plans? 

## Important issues for BCBS plans:

**Technology must be  covered **
**	****	****by the member contract**

## Important issues for BCBS plans

***Technology must meet normal regulatory standards ***
**FDA**
**CLIA**

## Important issues for BCBS plans

***Technology must be scientifically validated***
**Health insurance contracts generally exclude “investigative” or “experimental” technologies**
**BCBS plans define scientifically validated technology by standard criteria**

## Technology Assessment

**BCBSA Technology Evaluation Center established 1985**
**AHRQ Evidence-based Practice Center (EPC) since 1997**
- _[http://www.bcbs.com/tec](http://www.bcbs.com/tec)__ _
**TEC scientific criteria for assessing medical technologies**

## TEC Criteria

**The technology must have final approval from the appropriate governmental regulatory bodies.**
**The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.**

## TEC Criteria

**The technology must improve the net health outcome; and**
**The technology must be as beneficial as any established alternatives.**
**The improvement must be attainable outside the investigational settings.**

## Important issues for BCBS plans 

***Technology must be cost-effective***

## Slide 16

## Importance of Evidence Assessment

**SACGT emphasized critical role of data gathering and analysis:**
***“******Initial knowledge of the clinical validity of a genetic test is essential to assess its safety and efficacy. . . Researchers and test developers should gather and share data on the clinical validity and utility of genetic tests.**** “*

**Notes:**
From Enhancing the Oversight of Genetic Tests:
Recommendations of the SACGT  July 2000

Clinical validity, particularly predictive value, is influenced by the prevalence of the condition in the population.  Assessing clinical validity may be particularly challenging in the case of tests for rare diseases.  This is because gathering statistically significant data may be difficult, as relatively few people have these diseases.  Thus, prevalence may be a factor in determining how much data on test performance should be available before a test is offered in patient care.

For many genetic tests, particularly those that are predictive or presymptomatic, knowledge of the test’s clinical validity may be incomplete for many years after the test is developed.  When information that may affect clinical validity is incomplete, the potential harms of the test may increase and must be considered more carefully. 

Since data sharing and analysis are critical, relevant DHHS agencies should work collaboratively with researchers and test developers to advance data collection and provide this information to health care providers and the public.  Initial exploratory data collection efforts among DHHS agencies, which have been coordinated by CDC, have been of value and should continue.  DHHS agencies should involve relevant experts, organizations, and public representatives in data collection efforts.  Appropriate and timely data collection could contribute to a variety of assessments that would be critical to evaluating genetic tests, such as 1) comparative analyses of information gathered from existing literature sources; 2) pilot projects to assemble and compare data from published and unpublished sources; and 3) formal technology assessments.  The results of such assessments should be made publicly available in a timely manner.

Laboratories should be encouraged or required to make pre- and post-marketing data on genetic tests available in a timely, accurate, and understandable manner.  
 Post-market data collection can enhance understanding of current applications of a genetic test and is important for any expansion of the use of a genetic test beyond the initial indications approved when the test is made available.  Laboratories providing clinical genetic services should commit to post-market data collection efforts. 

## Regulatory gap

**CLIA regulates laboratory quality**
**FDA regulates analytical performance and manufacturing quality**
**Who evaluates clinical effectiveness?**

## Sources of Evidence Summaries

- BCBSA Technology Evaluation Center
- Other technology assessment groups:  Hayes, ECRI, (AHRQ)
- GeneTests – GeneReviews _[http://](http://www.genetests.org/)__[www.genetests.org](http://www.genetests.org/)__[/](http://www.genetests.org/)_
- HuGENetTM _[http://](http://www.cdc.gov/genomics/hugenet/default.htm)__[www.cdc.gov/genomics/hugenet/default.htm](http://www.cdc.gov/genomics/hugenet/default.htm)_
- ACCE Project** **_**[http://](http://www.cdc.gov/genomics/info/perspectives/files/testACCE.htm)**__**[www.cdc.gov/genomics/info/perspectives/files/testACCE.htm](http://www.cdc.gov/genomics/info/perspectives/files/testACCE.htm)**_
- Professional organizations e.g. ACMG, ASCO

## Assessment of Diagnostics

**Focus on patient outcomes**
**Analytic validation ****≠**** clinical validation**
**Direct vs. indirect chain of evidence**
**e.g. HIV RNA quantitation**
**↓****HIV RNA ******** ↑ CD4**
** ****↑ ****CD4 ******** ↑ Patient outcomes**

## TEC Assessments of Genetic Testing

**Genetic Testing for HFE Gene Mutations Related to Hereditary Hemochromatosis (2002)**
**Other**
**BRCA (breast cancer, 1997)**
**APC, HNPCC (colon cancer, 1998)**
**Apo E (Alzheimer’s, 1999)**

## Clinical Implementation of New Genetic Tests

**Tests launched in advance of evidence**
**When information on clinical validity is incomplete, harms may increase**** **

## Are evidence requirements for genetic tests for rare diseases different?

**Low prevalence********increased difficulty in gathering data**
- Funding
- Few centers able to study
- Need cooperation among US, international centers
- Affected population may be further stratified by variations in penetrance, severity

## Counter-argument

**Small sample size may be more representative of the affected population**
**If outcomes uniform, can get a good result with fewer numbers**
**A chronic disease course may result in a sufficiently high prevalence for study**
**Patients may go to fewer expert referral centers********easier to recruit**

## Counter-argument

**Potential for cooperation within the genetic disease community **
**Model:  pediatric oncology**
**Genetic testing may identify patients with lesser forms of disease who would not have been previously diagnosed; what is the evidence that identification and treatment are beneficial?**
**Treating in the absence of evidence may not be better than no treatment at all!**

## Important issues for BCBS plans

***Technology must be a benefit covered by the contract***
***Technology must meet normal regulatory standards***
***Technology must be scientifically validated***
***Technology must be cost-effective***

## Payor Perspective

**Agree on a workable definition of “rare”**
**Apply regulatory standards to ensure quality**
**Emphasize evidence collection and technology assessment**
**Exceptions handled on a case by case basis**
**Decisions are made by individual payors**

## Slide 28