Drug Substitution in Transplantation
Recommendations to the Health Care Community

Abstract
Methods
Recommendations
Conclusions
Reference

Drug substitution has become common practice in medicine today As the cost-saving potential and efficacy of generic drugs have become more widely recognized, substitution has become standard for many managed care providers. Drug substitution may involve the substitution of one generation of a drug for another, the use of a different agent within the same class of drugs or the use of a generic formulation for a brand name product. Possible advantages involve lower cost and better compliance. Possible disadvantages include overdose, underdose and unexpected side effects. The ongoing development of new therapies and drugs in the field of transplantation raises these and other important concerns that warrant discussion.

The National Kidney Foundation (NKF) has a well-established history of serving as a neutral catalyst for the discussion of current issues and medical problems that directly affect patient outcomes and delivery of patient care. A conference on "Drug Substitution in Transplantation" was organized by the NKF in April 1998 to review the recent literature and to develop recommendations for the safe and effective use of generic immunosuppressant medications in solid organ transplant recipients.

Conference participants represented various disciplines involved in transplantation and included transplant physicians and surgeons, pharmacists, nurses, transplant coordinators, social workers, health economists and transplant recipients. Pharmacokinetic, therapeutic, ethical and economic issues involved in immunosuppressant drug substitution were explored to develop recommendations that would best serve individual patients within the realities of today's health care system.

ABSTRACT

Sandra Sabatini, PhD, MD, Ronald M. Ferguson, MD, PhD, J. Harold Helderman, MD, Alan R. Hull, MD, Beverly S. Kirkpatrick, MSW, LSW, Kathleen D. Lake, PharmD, FCCP, BCPS, William H. Barr, PhD, PharmD.

Specific safeguards to guide the approval process and substitution practices for generic immunosuppressive agents are necessary for the effective delivery of patient care. Currently, the Food and Drug Administration (FDA) requires the demonstration of bioequivalence of generic drugs to innovator drugs in normal healthy subjects, a criterion that may be insufficient for critical-dose drugs. For generic equivalents of critical-dose drugs and for innovator critical-dose drugs, there should be a requirement for replicate studies measuring intrasubject variability and subject-treatment interactions to establish that bioequivalence holds true. Extensive testing of generic drugs in all target patient types is impractical and should not be required. However, when evidence suggests that the bioavailability of a critical-dose drug may vary substantially in certain subgroups, the FDA should require a demonstration of bioequivalence of generic versions to innovator products in these representative target populations. Changes in the approval process for generics should be accompanied by more consistent suhstitution practices. Pharmacists should notify the prescribing physician and patient whenever a critical-dose drug (generic or brand name) is dispensed in a different formulation from the one the patient has been taking. Therapeutic substitution for such drugs should not be made unless approval has been granted by the prescribing physician. The health care provider should consider instituting appropriate monitoring whenever patients are switched between generic formulations or between innovator drugs and generic formulations. Patients should be well informed about generic substitutes so that they can participate in treatment choices.

METHODS

Approximately 45 invited conference participants were appointed to one of three work groups for the purpose of conducting their deliberations. The three areas of concentration

• Mechanisms of Action of Transplantation Drugs
• Generic Substitution
• Impact of Managed Care

Each work group was made up of approximately fifteen experts from diverse clinical disciplines and transplant patients. Participants of the conference discussed alternative formulations of current branded immunosuppressives, substitution of generics and the development of a system for monitoring such substitution.

in particular, participants deemed it important to make recommendations about generic substitution because of concerns expressed in the transplant community that the current bioequivalence requirements of the FDA for generic drugs are insufficient for assessing immunosuppressive transplant drugs. To address the topic knowledgeably, the participants reviewed key terms, the history of drug substitution, the evolution of bioequivalence testing, and historical perspectives on bioequvalence.

RECOMMEDATIONS

Limitations of Current Bioequivolence Testing

The FDA is aware of concerns about generic substitution and is reviewing its methodology for establishing. While the FDA has concluded that there are no documented cases in which an approved generic product could not be used interchangeably with the corresponding brand-name drug, there may be particular circumstances in which substitution of therapeutically equivalent drugs causes important differences in effect for individual patients.

• Critical-dose drugs, as defined by conference participants and the literature, share the following characteristics: narrow therapeutic ranges
• requirement of blood-level monitoring on dosing based on body weight or other highly individualized dosing requirements
• serious clinical consequences of overdosing (toxicity) or underdosing (lack of effect)
• steep dose-response relationship for either efficacy and/or toxicity.
• The immunosuppressive agents cyclosporine and tacrolimus should be included in lists of critical-dose drugs. "' In the future, new immunosuppressive agents should be evaluated to determine whether they also meet these criteria.
• For critical-dose drugs, replicate design studies to determine intrasubject variability and subject-by-formulation interaction should be required as part of the approval process for both innovator drugs and their generic counterparts.'' The application of the recently proposed changes in the FDA bioequivalence metric would satisfy these requirements.
• Since clinical results are the key endpoint, research efforts should be directed at finding practical indicators of clinical effects so that the actual therapeutic efficacy of drugs can be more readily compared.

Issues Surrounding the Relevance of Study Populations

Currently, bioequivalence is tested in healthy, young, usually male volunteers. However, drug absorption in healthy individuals may not accurately predict the absorption in patient subgroups.

• For critical-dose drugs, replicate design studies to determine subject-by-formulation interactions should be required as part of the FDA approval process for both innovator drugs and their generic equivalents. The application of the recently proposed changes in the FDA bioequivalence metric would satisty these requirements.
• The FDA should request that generic manufacturers obtain bioequivalence data in subpopulations of patients for whom, based on evidence in the literature, the drug is likely to exhibit biouvailability that differs substantially from the norm.

The Safe and Effective Use of Generic Immunosuppressant Drugs

The safe and effective use of generic immunosuppressant drugs must be accompanied by a system of checks and balances, and substitution practices should be regulated to ensure consistency in policy.

• The health care provider should educate the patient about generic drugs and should include the patient in the decision of whether to switch drugs.
• The pharmacist should inform the prescribing physician and patient whenever a prescribed immunosuppressive drug for a transplant patient is to be switched. No therapeutic drug substitution of a critical-dose drug should be allowed without the approval of the prescribing physician or the patient.
• Physicians should seek information about the bioequivalence data for the agents they prescribe. When informed physicians are concerned about maintenance of consistent drug regimens or about bioequivalence of generic drugs, they should exercise their option to request that substitution not be made (in whatever manner is necessary to do so in that state) for such prescriptions.
• Patients should be taught how to identity the prescribed dosage form, and they should be instructed to alert the physician if a drug is substituted.
• The FDA should require that the appearance of all medications be unique and easily identifiable to help patients distinguish among drug products.
• Because of the potential consequences arising from differences in bioavailability or intrasubject variability with different products of critical-dose drugs, physicians should consider instituting appropriate monitoring (including blood levels if necessary) whenever patients are switched from one generic formulation to another, from an innovator drug to a generic, or from a generic to an innovator.
• The health care team should report adverse events with innovator and generic drugs to the FDA and the drug's manufacturer, and document this information in the patient's records. The prescriber should also consider informing third-party carriers.

CONCLUSION

Conference participants were concerned about the exclusion of certain immunosuppressive drugs from lists of critical-dose drugs, the applicability of currently used bioequivalence standards for special populations, and the difficulties encountered with substitution. Of particular concern was that the pharmacokinetic profiles of critical-dose generic drugs among subpopulations of transplant patients may differ substantially from those found in normal, healthy volunteers. These differences may lead to unanticipated differences in clinical response when generic drugs are substituted for innovator drugs in these subpopulations.

Because safe and effective generic immunosuppressive drugs have many potential cost-related benefits, the conference participants welcomed their introduction in the field of transplantation. However, certain safeguards must be adopted to prevent poor outcomes from inappropriate generic substitution of these drugs. Of first priority is scrutiny of the approval process. It is recommended that the FDA hold narrow therapeutic range drugs to more stringent standards of bioequivalence assessment than those used for other therapeutic classes, requiring that the drug manufacturer conduct replicate studies of intrasubject variability and subject-by-formulation interactions in addition to conventional bioavailability studies. Furthermore, the generic manufacturer should be required to demonstrate bioequivalence in target populations in which the innovator drug has shown substantial pharmacokinetic variation. Once approval has been granted for a given drug, consistent substitution practices should be adopted by all parties involved in the care of transplant patients as part of their shared responsibility for the safe and effective use of these drugs.

REFERENCE
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DRUG SUBSTITUTION IN TRANSPLANTATION
STEERING COMMITTEE

Sandra Sabatini. PhD. MD [Chair], Texas Tech University Health Sciences Center, Lubbock. TX

Ronald M. Ferguson, MD, PhD Ohio State University Columbus. OH

J. Harold Helderman, MD Vanderbilt University Medical Center Nashville, TN

Alan R. Hull. MD Renal Management, Inc Dallas, TX

Beverly S. Kirkpatrick, MSW. LSW, Albert Einstein Medical Center, Philadelphia, PA

Kathleen D. Lake. PharmD. FCCP, BCPS University of Michigan Medical Center Ann Arbor, Ml

William Barr, PhamD, PhD (Special Consultant) Virginia Commonwealth University Richmond, VA


CONFERENCE PARTICIPANTS

George Aronoff. MD, Universily ol- Louisville, Louisville. KY

Carolyn Atkins RN. BS. CNN Chidren's Medical Center of Dallas, Dallas. TX

Mark Barr. MD USC Cardiothoracic Surgery Los Angeles. CA

E ileen Prcwcr. MD, Texas Children's Hospital, Houston , TX

Gill Burckart. Pharm, D University of Pittshurgh, Pittshurgh. PA

Bill Coleman, Brooklyn, NY

Susan B. Conley. MD, St Christopher's Hospital, Philadelphia. PA

Jenny Corkill, RN, Crofton. MD

Nicholas Feduska. MD Ochsner Transplant Center New Orleans, LA

Roy First. MD Universily of Cincinnati Cincinnati, OH

Thomas Foster, PharmD University of Kentucky Medical Center Lexington. KY

Osama Gaber, MD University of Tennessee Memphis, TN

Kally Heslop Salt Lake City, UT

Larry Hunsicker, MD University of lowa Hospitals lowa City. IA

Anne Marie Jones, MSN Albert Einstein Med-Transplant Philadelphia, PA

Mark L. Jordan, MD University of Pittsburgh Pittsburgh. PA

Janet Karlix, PhD University of Florida Gainesville, FL

Fredenck Kaskel, MD. PhD Division of Pediatric Nephrology Stony Brook, NY

Goran B. Klintmalm, MD. PhD Baylor Institute of Transplantation Sciences Dallas, TX

Jerry McCauley, MD University of Pittsburgh Pittsburgh. PA

Roben Niemann Health Care Financing Administration Baltimore. MD

Ali Olyaei, PharmD Oregon Health Sciences University Ponland. OR

Mark Pescovitz, MD Indiana University Medical Center Indianapolis. IN, William Pfaff. MD, Universitv of Flonda Gainesville. FL

Raymond Pollack. MD University of Illinois Chicago. IL

Anita Principe. R.N Montefiore l\ledical Center Bronx, NY

Melissa Rau. ACSW, LMSW Transplant Institute Research Hospital Kansas City..MO

Kris Robinson Amencan Association of Kidney Patients Tampa, FL

Ron Shapiro, MD, University of Pittsburgh Medical Center, Pittsburgh, PA

Drew Silvemman, PharmD Tampa General Healthcare Tampa, FL

Alexis Southwonh, MSW, LCSW-C Glen Bumie, MD

Vivian Tellis, MD Montefiore Medical Center Bronx, NY

Laurel Wiliams Todd, RN, MSN. CCTC University of Nebraska Omaha, NE

Vanessa Underwood, BS, AFAA, ACE Plaistow, NH